Hearing loss in children and young adults is very often due to inherited mutations in still-unknown genes. Of the approximately 100 genes involved in hearing loss, 35 have been mapped and only 8 cloned so far. The normal counterparts of the genes responsible for inherited deafness must be critical to the normal development of hearing. Understanding the normal function of these genes is the first step in developing new approaches to treating sensorineural deafness. The most valuable resource for identifying these genes are persons from large families with carefully diagnosed inherited hearing loss and properly constructed genealogies who are willing to participate in genetic studies. Two extended kindreds from Israel are ideal. Family X is a 5-generation Jewish family with X-linked congenital deafness. Family N is a 4-generation Jewish family with all ancestors from the same endogamous ancient Jewish community in Mosul, Iraq. Members of Family N have autosomally inherited, progressive deafness. All deaf persons and their informative hearing relatives in both families are participants in the study, with informed consent, clinical information, and DNA obtained by Dr. Avraham. Our goals are to fine map (on the X chromosome) and clone the gene responsible for inherited loss in Family X, and to map and clone the autosomal gene responsible for inherited hearing loss in Family N. This project grow from our successful collaboration in mapping and cloning POU4F3, the gene responsible for inherited hearing loss in another large Israeli kindred. The study of Families X and N will offer Dr. Avraham experience with additional approaches to human gene mapping and positional cloning: homozygosity mapping, rapid thoughput genome-wide genotyping, the statistical basis of linkage analysis, and sample sequencing of genomic regions. Dr. Avraham s laboratory undertakes many elements of these approaches already and through this FIRCA is in an ideal position to become fully autonomous in genetic analysis.